Recent advances in medical procedures such as angioplasty continue to increase the use of endovascular stents in a variety of treatments for unblocking bodily lumens and restoring their function. With generally open tubular structures, stents often have apertured or lattice-like walls of a metallic or polymeric base, and can be either balloon expandable or self-expanding. An exemplary stent is deployed by mounting the stent on a balloon portion of a balloon catheter, positioning the stent in a body lumen, and expanding the stent by inflating the balloon. The balloon is then deflated and removed, leaving the stent in place. Stents help reduce the probability and degree of vessel blockage from restenosis.
Stents coated with protective materials and bioactive drugs are available commercially and have been shown to increase the effectiveness of stenting procedures and to control drug-elution properties. Medical research indicates a greater effectiveness of vascular stents when stents are coated with pharmaceutical drugs that help prevent or treat medical conditions such as restenosis and thrombosis. Stent coatings provide localized therapeutic pharmacological agents and treatment of a vessel at the site being supported by the stent to deliver patent effects at the site where they are most needed. The localized levels of the medications can be elevated, and therefore potentially more effective than orally or intravenously delivered drugs. Furthermore, drugs released from tailored stent coatings can have controlled, timed-release qualities, eluting their bioactive agents over hours, weeks or even months. Stent coatings typically have a drug or active agent, which has been dissolved or dispersed throughout the polymeric material and physically constrained within the polymer made from polyurethane, polyester, polylactic acid, polyamino acid, polyorthoester, or polyphosphate ester. The sustained release of drugs generally relies upon either degradation of the polymer or diffusion through the polymer to control the elution of the compounds.
Stents and other endovascular devices often undergo significant flexion or expansion during their delivery and deployment, and therefore, drug polymers that coat them need to be mechanically pliant. A stent deployed by self-expansion or balloon expansion is accompanied by a high level of bending at portions of the stent framework, which can cause cracking, flaking, peeling, or delaminating of many candidate drug polymers when the stent diameter is increased by threefold or more during expansion. In addition, any step within the process for coating a pre-deployed stent should not cause a drug-polymer to fall off, crystallize or melt. Chudzik and others disclose a flexible coating composition to address the need for pliancy in “Bioactive Agent Release Coating,” U.S. Pat. No. 6,344,035 issued Feb. 5, 2002. The bioactive agent or drug is in combination with a mixture of polymers such as poly(butyl methacrylate) and poly(ethylene-co-vinyl acetate). Polymers for use as stent coatings need to demonstrate characteristics of biocompability, good drug release as well as flexibility.
Drug polymers coatings for stents need to have polymer biocompatibility, satisfactory mechanical properties such as durability and integrity during roll down and expansion of the stent, and correct release profiles for the drugs. Coatings with a polymer or combination of a polymer and a pharmaceutical agent or drug can be applied to a stent with application techniques such as dipping, spraying, painting, and brushing.
In many of the current medical device or stent coating methods, a composition of a drug and a polymer in a common solvent is applied to a device to form a substantially uniform layer of drug and polymer. Techniques have been developed to micronize drugs into small particles so that drugs can be suspended in the polymeric solution. While these techniques can be attractive, micronization is often time consuming, and may result in a degradation or loss of desired therapeutic properties of the drug. A method of using micronized drugs and layering a drug-coated stent using pharmacological and polymeric agents is described by Guruwaiya and others in “Method of Layering a Three-Coated Stent Using Pharmacological and Polymeric Agents,” U.S. Pat. No. 6,251,136 issued Jun. 26, 2001. A pharmacological agent is applied to a stent in dry, micronized form over a sticky base coating. A membrane-forming polymer, selected for its ability to allow the diffusion of the pharmacological agent therethrough, is applied over the entire stent.
A method of applying drug-release polymer coatings that uses solvents is described in “Method of Applying Drug-Release Coatings,” Ding et al., U.S. Pat. No. 5,980,972 issued Nov. 9, 1999. A polymer is dissolved in one solvent and a drug is dissolved or suspended in a similar or different type of solvent. The solutions are applied either sequentially or simultaneously onto the devices by spraying or dipping to form a substantially homogenous composite layer of the polymer and the biologically active material.
Spraying coating is a currently preferred method for coating stents with drug polymers, which can result in a significant amount of drug-polymer spray material lost during the process. When expensive drugs are used in these coatings, the use of spray coating may be costly.
Dip coating was common with early designs of stents and other medical-device designs, which typically had relatively open construction fabricated from wires or from ribbons. Dipped coatings with relatively low coating weights, for example, coatings with about 4% polymer, were used with some occurrences of bridging or webbing of the coating in the open spaces or slots between the structural members of the device. Such coating was performed by manually dipping the stent in a liquid, and then removing the stent and drying it. The dipping process requires care to avoid excess liquid on the stent framework or inconsistent drying of the liquid, otherwise the apertures can become blocked unnecessarily. Applying one thick coating tends to exacerbate webbing and bridging problems. Increasing the solids content of the coating solution also increases webbing and bridging between the struts. Any coating method needs to avoid webbing, as well as control the weight and thickness of the coating.
Researchers and manufacturers of stents recognize the problems of webbing and having excess coating material on stent struts. For example, a manual-dipping process step that blows excessive material off the open framework of a tubular stent is disclosed in “Coating” by Taylor et al., U.S. Pat. No. 6,214,115 issued Apr. 10, 2001. The process addresses the problems of inconsistent drying and blockage of openings. Another dipping process that addresses the issues of blockage and bridging between the stent struts is disclosed by Hossainy and others in “Process for Coating Stents,” U.S. Pat. No. 6,153,252 issued Nov. 28, 2000. Flow or movement of the coating fluid through the openings in the perforated medical device is used to avoid the formation of blockages or bridges. The flow system may use a perforated manifold inserted in the stent to circulate the coating fluid, or may place the stent on a mandrel or in a small tube that is moved relative to the stent during the coating process.
Newer stents that are of less open construction, such as catheter-deployed, self-expanding stents are more difficult to coat evenly using a dipping method. Nevertheless, one advantage of dip coating is the possibility of processing a greater number of stents in a more efficient manufacturing process.
A stent with a single coating of least one therapeutic agent is described by Sirhan and Yan in “Delivery or Therapeutic Capable Agents,” U.S. Patent Application Number 20020082679 published Jun. 27, 2002. Barry and others describe another polymer composition that can be used for delivering substantially water-insoluble drugs in “Loading and Release of Water-Insoluble Drugs,” U.S. Pat. No. 6,306,166 issued Oct. 23, 2001. A medical device is coated with one or more layers of a volatile organic solution comprising a polyvinyl aromatic polymer and the antineoplastic chemotherapy drug such as paclitaxel. In the descriptions of the forementioned coatings, dipping is given as one of the methods for applying the drug-polymer coating to the device, although the publications do not address the potential problem of webbing or bridging in the open areas of stent structures, particularly when multiple coats are applied.
Multiple dips can be used to build up the weight and thickness of the coating, but each subsequent dip may affect the coating already deposited. A coating can re-dissolve in a second coating solution, causing some loss of the first layer of coating. Also, applications of multiple dip coats from low concentration solutions can have the effect of reaching a limiting loading level as equilibrium is reached between the solution concentration and the amount of coating with or without a pharmaceutical agent. One such method that applies a plurality of relatively thin coatings on an open-lattice stent is disclosed in “Drug Release Stent Coating,” Ding et al., U.S. Pat. No. 6,358,556 issued Mar. 19, 2002. The stents are coated by dipping or preferably spraying the stent with a solvent mixture of uncured polymeric silicone material with a crosslinker and a finely divided biologically active species. The method includes a step for sterilizing with an inert argon gas plasma and exposure to gamma radiation.
A multiple-dip coating method that uses two or more incompatible polymer solutions to build up successive layers may avoid the load limitations of coating methods that employ one type of solvent, but it may lose the cost and time advantage of dipping coating over other coating techniques. Thus, a more beneficial multiple-dip coating technique for stents would not require the use of incompatible polymer solutions to solve the problem of previous coating layers being dissolved by the next layer of dipped drug polymer.
Accordingly, what is needed is an improved manufacturing method for dip-coating medical devices such as stents that can apply multiple drug-polymer coatings in a time-efficient manner while avoiding the leaching of a drug or polymer from a previous layer by the dipping solution constituents. An improved process provides coatings that are well adhered and flexible, as well as controls coating properties such as thickness, porosity, and smoothness. An improved stent with one or more drug-polymer coatings maintains mechanical integrity during its deployment, provides a desired elution rate for one or more drugs, and overcomes the deficiencies and limitations described above.